Aromatic and aliphatic hydrazone derivatives of 1-amino-4-diphenylalkylpiperazines



United States Patent ARQMATIC AND ALIPHATIC HYDRAZONE DE- RIVATIVES 0F1--AMlNO-4-DIPHENYLALKYL- PIPERAZINES I John W. Cusic, Skokie, andErnest F. Le Von, Morton Grove, IlL, assignors to G. D. Searle & Co.,Chicago, Ill., a corporation of Delaware No Drawing. Filed Apr. 4,1963,Ser. No. 270,525

Claims priority, application Republic of the Philippines,

Sept. 17, 1962, 4,397 13 Claims. (Cl. 260-240) The present inventionrelates to a group of compounds which are hydrazone derivatives of1-amino-4-diphenylalkylpiperazines and related compounds. Moreparticularly, it relates to compounds having the following generalformula Caz-(011;). R

X Ar R wherein Ar is selected from the group consisting of phenyl,tolyl, halophenyl, methoxyphenyl, trifluoromethylphenyl, and pyridyl; Xis selected from the group consisting of hydrogen and halogen; m is awhole number between 0 and 1 inclusive; n is a positive integer lessthan 3; R is selected from the group consisting of alkyl, alkenyl,cycloalkyl, cycloalkenyl, phenylalkyl, phenylalkenyl, and substituted orunsubstituted monocyclic, dicyclic, or tricyclic aryl radicals, or R canbe combined with R to represent polyalkylene so that RCOR' represents acyclic alkanone and represents a cyclic alkylidene radical such ascyclohexylidene; R can also be combined with R to give a biphenyleneradical; R is selected from the group consisting of hydrogen, methyl,phenyl, and, when combined with R, polyalkylene and biphenylene.

The halophenyl radicals referred to above with regard to Ar includefluorophenyl, chlorophenyl, bromophenyl, and iodophenyl. Likewise, thehalogens referred to with regard to X include fluorine, chlorine,bromine, and iodine.

More particularly, R in the above formula can represent an aromatichydrocarbon radical containing up to 14 carbon atoms such as phenyl,tolyl, naphthyl, and anthryl; a halophenyl radical such as fluorophenyl,chlorophenyl, bromophenyl, and iodophenyl; hydroxyphenyl,dihydroxyphenyl; a (lower alkanoyloxy)phenyl radical such asacetoxyphenyl, and propionyloxyphenyl; an alkoxyphenyl radical such asmethoxyphenyl, dimethoxyphenyl, and trimethoxyphenyl;methylenedioxyphenyl; a dialkylaminoalkoxyphenyl radical such asdiethylaminoethoxyphenyl; nitrophenyl; dimethylaminophenyl; (lowerallianamido)phenyl such as acetamidophenyl and propionamidophenylwherein the alkanamido portion contains up to six carbon atoms;carboxyphenyl, cyanophenyl, styryl; phenyl(lower alkyl) radicals such asbenzyl and phenethyl wherein the lower alkyl portion contained up to 6carbon atoms; lower alkyl radicals such as methyl, ethyl, propyl, butyl,and like alkyl radicals containing up to 6 carbon atoms; lower alkyleneradicals such as vinyl, propenyl, allyl and like alkylene radicalscontaining up to 6 carbon atoms; cycloalkyl and cyloalkenyl radicalssuch as cyclohexyl and cyclohexenyl; benzhydryl, biphenylyl and, whencombined with R, biphenylylene and polyalkylene radicals such aspentamethylene.

In addition to the substituted phenyl groups referred to above, itshould be recognized that R can represent other polysubstituted phenylradicals such as xylyl, tri- "ice methylphenyl, difiuorophenyl,dichlorophenyl, hydroxy tolyl, fluorotolyl, methoxytolyl,hydroxymethoxyphenyl, and similar polysubstituted phenyl groups. Furthermore, radicals under R such as phe'riylflower alkyl), styryl, naphthyl,and biphenylyl can be further substituted with groups such as methyl,methoxy, halogen, and similar groups.

The compounds of this invention are useful because of theirpharmacological properties. In particular, they possess anti-conwlsantactivity. This is demonstrated by their inhibition ofpentylenetetrazole-induced convulsions and their antagonism ofelectroshock seizures. activity is unexpected because the correspondingl-benzyl compounds either possess relatively weak anti-convulsantactivity or lack this activity entirely. In addition, the presentcompounds are inhibitors of hepatic cholesterol synthesis. They have thepower to inhibit incorporation of mevalonic acid into unsaponifiablecholesterol precursors.

A preferred embodiment of this invention consists of those compounds inwhich R is an oxygen-substituted phenyl radical, i.e., wherein R ismethoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, or, especially,hydroxyphenyl and methylenedioxyphenyl.

Another preferred embodiment of this invention are those compounds inwhich R is an aromatic hydrocarbon radical containing up to 10 carbonatoms. Phenyl, tolyl, and naphthyl illustrate this embodiment.

A further preferred embodiment of this invention are those compounds inwhich R is cyanophenyl.

Another preferred embodiment of this invention are those compounds inwhich R is halophenyl such as fluorophenyl, chlorophenyl, bromophenyl,and iodophenyl.

The organic bases of this invention form pharmaceutically acceptable,non-toxic, acid addition salts with a variety of organic and inorganicacids. Such salts are formed with acids such as sulfuric, phosphoric,hydrochloric, hydrobromic, hydroiodic, sulfamic, citric, lactic,

maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic,ascorbic, and related acids. A

The compounds of this invention can be prepared by the condensation ofthe appropriate aldehyde or ketone with a1-substituted-4-aminopiperazine. The reaction is carried out in an inertsolvent. Examples of solvents useful for this purpose are alcohols suchas ethanol and 2-propanol or aromatic hydrocarbons such as benzene andtoluene. A small amount of acid can be added to the reaction mixture tohelp catalyze the reaction. Acetic acid is an example of an acid usefulfor this purpose, and, actually, the reaction can also be carried outusing acetic acid as the solvent. When the above reaction is carried outin hydrocarbon solvents, it is desirable to remove the water from thereaction mixture as it is formed by means of an azeotrope trap. Incertain instances, an excess of the carbonyl compound reactant can beused as the solvent. The reaction is promoted by the use of elevatedtemperatures.

The compounds which constitute this invention and their preparation willappear more fully from a consid eration of the following examples whichare given for the purpose of illustration only and are not to beconstrued as limiting the invention in spirit or in scope. In theseexamples, quantities are in parts by weight unless parts by volume areindicated, temperatures are in degrees centigrade C.), and pressures arein millimeters of mercury (mm). The relationship between parts by volumeand parts by weight is the same as that between milliliters and grams.

The present application is a continuation-in-part of copendingapplication Serial Number 142,005, filed October 2, 1961, and nowabandoned.

This

3 Example 1 A mixture of 46 parts of 2-chlorobenzhydryl chloride, 50parts of piperazine, 30 parts of potassium carbonate, 3 parts of sodiumiodide and 480 parts of butanone is stirred and refluxed for 48 hours.The reaction mixture is filtered and the solvent is evaporated from thefiltrate. The residue is distributed between benzene and water and thebenzene layer is separated and washed with water. It is then extractedtwice with 3 N hydrochloric acid and the acid extract is washed withbenzene, alkalized, and extracted with benzene. The benzene solution iswashed and dried and the solvent is evaporated to give1-(2-chlorobenzhydryl)piperazine. I

If the above procedure is repeated using the appropriate substitutedchloride in place of the 2-chlorobenzhydryl chloride, the followingcompounds are obtained:

1- (4-iodobenzhydryl piperazine.

1-(4-chlorobenzhydryl)homopiperazine. In this case homopiperazine isused in place of pipera'zine 1-(Z-methylbenzhydryl)piperazine.

1- oc- (2-pyridyl benzyl] piperazine.

1- [oc- 3 -pyridyl benzyl] piperazine.

Example 2 To a suspension of 200 parts of l-benzhydrylpiperazine and 400parts of water is added gradually 190 parts of concentrated hydrochloricacid with cooling in an ice bath. The resultant mixture is stirred for 1hour, the insoluble material is filtered off and the filtrate is cooledto C. A solution of 57 parts of sodium nitrite and 200 parts of water isadded portionwise over a period of 3 hours. The precipitate which formsis filtered off, washed with dilute hydrochloric acid and driedovernight. Recrystallization of the product from 790 parts of absoluteethanol gives the purified hydrochloride which is then suspended in 1000parts of water and 1760 parts of benzene. A slight excess of aqueoussodium hydroxide is added and the mixture is stirred until all the solidhas dissolved. The benzene solution is separated, washed with water, anddried and the solvent is evaporated. The residual base is recrystallizedfrom heptane to give 1- benzhydryl 4 nitrosopiperazine melting at about110- 111 C.

If the above procedure is repeated using the appropriate substitutedl-benzhydrylpiperazine, the following compounds are obtained:

1-(2-chlorobenzhydryl)-4-nitrosopiperazine melting at about 117119 C.

1- (4-iodobenzhydryl -4-nitrosopiperazine.

1-(2-methylbenzhydry1)-4-nitrosopiperazine melting at about 104-106 C.after recrystallization from hexane.

1-(4-chlorobenzhydryl)-4-nitrosoh'omopiperazine.

Example 3 A solution of 86 parts of 1-(4-chlorobenzhydryl)piperazine and500 parts of water containing 24 parts of hydrogen chloride isnitrosated with 21 parts of sodium nitrite in 100 parts of water. Thereaction mixture is made alkaline by the addition of sodium hydroxidesolution and an oily layer forms. The oily product is separated andcrystallized from a mixture of 45 parts of ethyl acetate and 700 partsof n-heptane. The resultant solid is recrystallized from a mixture of2-propanol and hexane and then from a mixture of ethyl acetate andheptane to give 1-(4-chlorobenzhydryl)-4-nitrosopiperazine melting atabout 121123 C.

In a similar manner, 39 parts of 1-[a-(2-pyridyl)benzyl]piperazine isdissolved in 48 parts of concentrated hydrochloric acid and 150 parts ofwater and cooled to 5 C. A solution of 17 parts of sodium nitrite in 85parts of Water is added portionwise while maintaining the temperature atabout 5 C. The resultant mixture is stirred for 4 hours with coolingbefore it is warmed to room temperature and made alkaline with dilutesodium hydroxide solution. The resultant mixture is extracted with etherand the ether extract is dried and the solvent is removed to give1-[a-(Z-pyridyDbenzyl]-4-nitrosopipera'zine.1-[a-(3-pyridyl)benzyl]-4-nitrosopiperazine is obtained from1-[a-(3-pyridyl)benzyl]piperazine in the same way.

Example 4 4-chloro-4'-methylbenzhydryl chloride is prepared by refluxinga mixture of 4-chloro-4-methylbenzhydrol with thionyl chloride and atrace of pyridine in chloroform- Distillation of the reaction mixturegives the desired product boiling at about 165175 C. at 0.1-0.4 mm. andmeltingat about 43-45.5 C.

A mixture of 10 parts of 4-chloro-4-methylbenzhydryE chloride, 6 partsof l-nitrosopiperazine, 10 parts of pot assium carbonate, and 1 part ofsodium iodide in 160' parts of 2-butanone is stirred and refluxed for 4days. The reaction mixture is filtered and the solvent is evaporatedfrom the filtrate. The resultant residue is dissolved in benzene and thebenzene solution is washed with two portions of 10% acetic acid and thenwith water and dried. Evaporation of the solvent from the benzenesolution leaves a residue which is recrystallized from parts of2-propanol to give 1-(4-chloro-4-methylbenzhydryl)-4-- nitrosopiperazinemelting at about -428" C. In the same way,1-(4-trifluoromethylbenzhydryl)-4-nitrosopiperazine is obtained from4-trifluoromethylbenzhydryl chloride and l-nitrosopiperazine.

In a similar manner, 5.5 parts of 4-fluorobenzhydryl chloride, 6 partsof l-nitrosopiperazine, 0.6 part of potassium iodide, 10 parts ofpotassium carbonate, and 200 parts of butanone are stirred at reflux for4 days. Isola-- tion of the product is carried out as indicated above,except that the acidic washes are omitted. In this case, the product is1-(4-fluorobenzhydryl)-4-nitrosopiperazine.1-(4-methoxybenzhydryl)-4-nitrosopiperazine is prepared from4-rnethoxybenzhydryl chloride and l-nitroso pipera zine by the sameprocedure.

Example 5 A mixture of 15 parts of 3-chlorobenzhydry1 chloride and 7.4parts of l-nit-rosopiperazine in 245 parts of dry pyridine is refluxedfor 1.5 hours. The solvent is evaporated from the reaction mixture andthe residue is distributed between benzene and water. The benzene layeris separated and dried over potassium carbonate and the solvent isevaporated to give a brown oil which is crude 1-(3-chlorobenzhydryl)-4-nitrosopiperazine. This material is suitable forreduction withoutadditional purification.

Example 6 A mixture of 22 parts of 4,4-dichlorobenzhydryl chloride and10 parts of l-nitroso piperazine in 180 parts of triethylamine isrefluxed for 6 days. The resultant mixture is diluted with 440 parts ofbenzene and washed with 6 portions of water, twice with 10% aqueousacetic acid, and twice more with water. The benzene solution is driedover potassium carbonate, the solvent is evaporated, and the residue isrecrystallized from n-hexane and then from ethyl acetate to give1-(4,4'-dichlorobenzhydryl)-4- nitrosopiperazine melting at about 156160C.

Example 7 A solution of 10 parts of 1-benzhydryl-4-nitrosopiperazine inparts of anhydrous ether and 5 parts of benzene is added portionwise toa suspension of 1.9 parts of lithium aluminum hydride in 140 parts ofether. The reaction mixture is stirred for 1 hour at room temperatureand then refluxed and stirred for 2 hours. The reaction mixture iscooled in an ice bath and excess lithium aluminum hydride is decomposedby the addition of ethyl acetate. The reaction mixture is hydrolyzed by:the dropwise addition of 2 parts of water, 2 parts of 20% sodiumhydroxide solution and 6 parts of water. The inorganic salts arefiltered ofl? andwashed with ether- In this '-case tetrahydrofuran isused in place of benzene to dissolve the nitroso compound.

1-(3-chlorobenzhydryl)-4-aminopiperazine. The hydrochloride of thiscompound melts at about l80-190 C. with decomposition.

1-(4-chlorobenzhydryl)-4-aminopiperazine melting at about 11-6l21 C.

1- 4-chlorobenzhydryl -4-aminohornopiper azine.

1 (4,4 dichlorobenzhydryl)-4-aminopiperazine. A mixture oftetrahydrofuran and ether (2:5) is used as the solvent for the reductionin this instance.

1- 4-io dobenzhydryl -4-aminopiperazine.

1- (Z-methylbenzhydryl -4-aminopiper azine.

1 (4-chloro-4-methy1benzhydryl)-4-aminopiperazine. In this casetetrahydrofuran is used in place of benzene to dissolve the nitrosocompound.

1-(4-methoxybenzhydryl)-4-aminopiperazine. A 1:2 mixture oftetrahydrofuran and ether is used as the solvent for the reduction.

l- (4-trifluoromethylb enzhydryl) -4-aminopiperazine.

1-[a-(2-pyridyl)benzyl]-4-aminopiperazine. In this case the reaction iscarried out in tetrahydroturan and the crude product is used withoutfurther purification.

1- [a-( B-pyridyl) benzyl] -4-aminopiperazine.

Example 8 A mixture of 110 parts of triethylamine, 3 6 parts oflnitrosopiperazine and 375 parts of chloroform is heated to 60-65 C. Asolution of 70 parts of diphenyl-acetyl chloride in 150 parts ofchloroform is then added portionwise. The resultant mixture is heated at70-75 C. for an additional 3 hours and it is then cooled to roomtemperature. An additional 25 parts of chloroform is added and theresultant mixture is washed with several portions of water. Thechloroform layer is dried and the solvent is evaporated to give thecrude solid product. This solid is washed with ether to givel-diphenylacetyl- 4-nitrosopiperazine melting at about 149-151 C.

16 parts of 1-diphenylacetyl-4-nitrosopiperazine is placed in thethimble of a continuous extractor and a solution of 15 parts of lithiumaluminum hydride in 875 parts of ether is placed in the flask of theextractor. The ether solution is refluxed for 21 hours to bring thenitroso compound into contact with the reducing mixture. The ethersolution is then cooled to 5 C. and decomposed by the cautious additionof water. The ether layer is then separated and dried and the solvent isevaporated to give 1-(2,2-diphenylethyl)-4-aminopiperazine as an oil.This product is used without further purification.

If 4-chlorodiphenylacetyl chloride is substituted for the diphenylacetylchloride and the procedure of the preceding two paragraphs is repeated,there is obtained 1- [2- 4-chlorophenyl) -2-phenylethyl]-4-aminopiperazine.

Example 9 To a solution of 10 parts of 1-(4-chlorobenzhydryl)-4-aminopiperazine in 119 parts of warm 2-propanol is added 3.6 parts ofbenzaldehyde. The solution is boiled for 5 minutes and allowed to coolslowly. A pale yellow solid crystallizes from the solution and it isrecrystallized from Z-propanol to give 1-(4-chlorobenzhydryl)-4-benzalaminopiperazine melting at about 97-99 C. This compoundhas the following formula Example 10 1-benzhydry1-4-aminopiperazine isreacted with benzaldehyde according to the procedure described inExample a 9. In this case, the product is1-benzhydryl-4-benzalaminopiperazine melting at about 13ll32 C.

In the same way, 1-(2-methylbenzhydryl)-4-aminopiperazine is reactedwith benzaldehyde to give 1-(2-methylbenzhydryl)-4-benzalaminopiperazine melting at l07-11l C.

Example 11 scribed in Example 9, the product is1-(3-chlorobenzhydryl)-4-benzalaminopiperazine melting at about 137 C.

Likewise, 1-(4-iodobenzhydryl)-4-aminopiperazine reacts withbenzaldehyde to give 1(4-iodobenzhydryl)-4- benzalaminopiperazine.

In the same manner, 1-(4-fluorobenzhydryl)-4-aminopiperazine is reactedwith benzaldehyde. However, absolute ethanol containing 0.1 part ofacetic acid replaces the 2-propanol as the solvent. The product of thereacr tion is 1-(4-fluorobenzhydryl)-4-benzalaminopiperazine melting atabout 114116.5 C.

Example 12 The procedure of Example 9 is repeated using 1-(4,4-dichlorobenzhydryl)-4-aminopiperazine and benzaldehyde as the reactants,ethanol as the solvent, and, additionally, 0.1 part of acetic acid. Theproduct is 1-(4,4'-dichlorobenzhydryl)-4-benzalaminopiperazine meltingat about 152l54 C. when dried at 100 C. for 3 hours under vacuum.

In the same way, 1-(4-trifluoromethylbenzhydryl)-4- piperazine reactswith benzaldehyde to givel-(4-trifiuoromethylbenzhydryl)-4-benzalaminopiperazine melting at about121123 C. after recrystallization from absolute ethanol.

Example 13 benzhydryl)-4-benzalaminopiperazine melting at about Example14 1- (2,2-diphenylethyl -4-aminopiperazine and l- [2- (4-chlorophenyl)-2-phenylethyl]-4-aminopiperazine are each reacted withbenzaldehyde, using Z-propanol as the solvent and 0.1 part of aceticacid as catalyst, to give, respectively,1-(2,2-diphenylethyl)-4-benzalaminopiperazine melting at about 117-118C. and 1-[2-(4-chlorophenyl)- 2-phenylethyl]-4-benzalarninopiperazinemelting at about 112-114 C. The procedure used is essentially the sameas that described in Example 9.

In the same manner, 1-benzhydryl-4-aminopiperazine is reacted with4-phenylbenzaldehyde to give l-benzhydryl-4-(4-phenylbenzalamino)piperazine which melts at about 169-170" C. after recrystallization from2-propanol.

Likewise, 1- oc- Z-pyridyl benzyl] -4-aminopiperazine is reacted withbenzaldehyde to give l-[a-(Z-pyridyDbenzyl]-4-benzalaminopiperazinemelting at 141142 C.

7 Example 15 A mixture of parts of 1-benzhydryl-4-aminopiper azine, 3.5parts of Z-naphthaldehyde, and 264 parts of benzene is refluxed in areaction vessel equipped with a reflux condenser and an azeotrope trap.Refiuxing is continued until no more water distills from the mixture.The benzene solvent is then evaporated from the solution and the residueis recrystallized from benzene to give a crude product which is furtherrecrystallized from a mixture of benzene and hexane. This givesl-benzhydryl- 4 (2 naphthylmethyleneamino)piperazine melting at about168-1685 C.

If 3.5 parts of l-naphthaldehyde is substituted for theT2-naphthaldehyde and the above procedure is repeated, the product isl-benzhydryl 4 (1 naphthylmethyleneamino) piperazine melting at about165 C. This compound has the following formula Example 161-(2-cl1lorobenzhydryl)-4-aminopiperazine is reacted with benzaldehydeaccording to the procedure described 'in Example 15. The product isl-(2-chlor'obeitzhydryly 4-benzalaminopiperazine melting at about147-150" C.

Example 17 If the procedure of Example 9 is repeated using an equivalentquantity of 1--(4-chlorobenzhydryl)-4-arnino homopiperazine in place ofthe 1-(4-chlorobenzhydryl)- 4-aminopiperazine, the product obtained isl-(4-chlorobenzhydryl)-4 benzalaminohomopiperazine melting at about138142 C.

Example 18 1-benzhydryl-4-aminopiperazine is reacted with acetophenoneaccording ot the procedure described in Example 9. The product is1-benzhydryl-4-(oz-methylbenzalamino)piperazine melting at about 162-l64C. This compound has the following formula Example 19l-benzhydryl-4-aminopiperazine is reacted with 2-tolu aldehyde accordingto the procedure described in Example 9. The product obtained is1-benzhydryl-4-(2- methylbenzalamino)piperazine melting at about 130-131 C.

If 1-benzhydryl-4-aminopiperazine is reacted with 4- tolualdehydeaccording to the procedure described in Example 9, the product obtainedis 1-benzhydryl-4-(4- methylbenzalamino)piperazine melting at about 177-178 C.

Example 20 The procedure of Example is repeated using an equivalentquantity of 4-fiuorobenzaldehyde in place of the 2-naphthaldehyde. Theproduct obtained is l-benzhydryl 4 (4 fiuorobenzalamino)piperazinemelting at about 128-130" C.

Example 21 Z-chlorobenzaldehyde is reacted with 1-benzhydryl-4-aminopiperazine according to the procedure described in Example 9. Inthis case the product is 1-benzhydryl-4- (2-chlorobenzalamino)piperazinemelting at about 165- 167 C.

If 3-chlorobenzaldehyde is reacted with l-benzhydryl- 4-amin0piperazineaccording to the procedure described in Example 9, the product is1-benzhydryl-4-(El-chlorobenzalamino)piperazine melting at about 107 C.

Likewise, 4-chlorobenzaldehyde is reacted withl-benzhydryl-4-aminopiperazine to give1-benzhydryl-4-(4-chlorobenzalamino)piperazine melting at about 148150C.

If 4-iodobenzaldehyde is reacted with 1-benzhydryl-4- aminopiperazineaccording to the procedure described in Example 9, the product isl-benzhydryl-4-(4-iodobenzalamino) piperazine.

Example 22 1-(2,2-diphenylethyl)-4-aminopiperazine and 1-[a-(2-pyridyl)benzyl]4-aminopiperazine are each reacted with4-hydroxybenzaldehyde, using 2-propanol as the solvent and 0.1 part ofacetic acid as catalyst, to give respectively, 1-(2,2-diphenylethyl) 4(4-hydroxybenzalamino)piperazine melting at about 148149 C. and1-[a-(2-pyridyl)- benzyl]-4-(4-hydroxybenzalamino)piperazine melting atabout 214-215 C. The procedure used is essentially the same as thatdescribed in Example 9. The latter compound has the following formula1-(4-chlorobenzhydryl 4 aminopiperazine is reacted with4-hydroxybenzaldehyde according to the procedure described in Example15. In this case, the crude product is recrystallized first from amixture of ethyl acetate and n-hexane and then from a mixture of ethylacetate and n-pentane. The product thus obtained, 1-(4-chlorobenzhydryl)-4- (4-hydroxybenzalamino piperazine containing /2 mole of ethylacetate, melts at about -1 17 C.

Example 25 Example 24 A mixture of 10 parts of 1-(4-chlorobenzhydryl)-4-aminopiperazine, 5 parts of piperonal, 2 parts of glacial acetic acid,and 530 parts of benzene is refluxed in a vessel provided with anazeotrope trap. Reflux is continued until the calculated amount of Waterhas separated. This requires about 2 hours. The reaction mixture iscooled, washed with aqueous sodium hydroxide solution and then withwater, and dried over potassium carbonate. The solvent is evaporatedfrom the solution under reduced pressure and the residual syrup iscrystallized from 2-propanol to givel-(4-chlorobenzhydryl)-4-(3,4-methylenedioxybenzalamino)piperazinemelting at about 128- 133 C.

If l-(2-chlorobenzhydryl)-4-aminopiperazine is reacted with piperonal inthe same manner, the product is 1-(2- *9 g chlorobenzhydryl) 4'(3,4methylenedioxybenzalarnino) piperazine. This compound has the followingformula Example 26 If an equivalent quantity of l-benzhydryl4-aminopiperazine is substituted for the l-(4-chlorobenzhydryl)-4-aminopiperazine and theprocedure of Example 25 is repeated, the productis l-benzhydryl-4-(3,4-methylenedioxybenzalamino)piperazine melting atabout 144-l45 C.

Likewise, if an equivalent quantity of 1-(4-chloro-4'-methylbenzhydryl)-4-aminopiperazine is substituted for the1-(4-chlorobenzhydryl)s4-aminopiperazine and the same procedure isrepeated, theproduct is l-(4-chloro- 4' -rnethylbenzhydry l) 4(3,4-methylenedioxybenzalamino) piperazine melting at about 180-181 C.

Example 27 4 parts of l-(2,2-diphenylethyl)-4-aminopiperazine, 2.2 partsofpiper-onal and 0.1 part of acetic acid in 40 parts of Z-propanol isheated on a steam bath for about 5 minutes. The resultant mixture isallowed to cool and the solid which forms is separated andrecrystallized from Z-piopanol to givel-(2,2-diphenylethyl)-4-(3,4-rnethylenedioxybenzalamino)piperazinemelting at about 131- 133" C.

In the same way, l-[2-(4-chlonophenyl)-2-phenylethyl]-4 aminopiperazineis reacted with piperonal to give 1- 2- (4chlorophenyl) -2-phenylethyl]-4- 3,4-methyl- 'enedioxybenzalamino)piperazine melting at about 143-145 C. This compound has the following formulahydryl-4-(2-methoxybenzalamino)piperazine melting at sweet about 146l48C.

Example The procedure of Example 9 is repeated using l-benzhydryl 4aminopiperazine and 2,4-dimethoxybenzaldehyde as the reactants. Theproduct is l-benzhydryle l- (2,4-dimethoxybenzalamino)piperazine.

Likewise, if the procedure of Example .9 is repeated using1-benzhydryl-4-aminopiperazine and 3,4-dimethoxybenzaldehyde as thereactants, the product isl-benzhydryl-4-(3,4-dimethoxybenzalamino)piperazine melting at aboutl76-177.5 C.

Example 31 1-benzhydryl-4 aminopiperazine is reacted with 3,4,5-trimethoxybenzaldehyde according to the procedure described in Example25. The product obtained is l-benzhydryl-4- 3 ,4,S-trimethoxybenzalaminopiperazine melting at about 163-165 C.

Example 32 If an equivalent quantity of vanillin is substituted for thebenzaldehyde and the procedure of Example 9 is repeated, the product isl-(4-chlorobenzhydril)-4-(4-hy droxy-3-methoxyb enzalamino piperazine.

Likewise, protocatechualdehyde reacts with1-(4-chlorobenzhydryl)-4-arninopiperazine to give 1-(4-chlorobenzhydryl)-4- 3,4-dihydroxybenzalamino) -piperazine.

Example 33 l-benzhydryl-4-aminopiperazine is reacted with4-(B-diethylaminoethoxy)benzaldehyde according to the procedure ofExample 25. Isolation of the product inthe usual manner givesl-benzhydryl-4-[4-(ddiethylaminoethoxy)- benzalamino1piperazine meltingat about 75-78 C. This compound has the followingformula CH CH Example28 A mixture of 6 parts of l-.[a-(2-pyridyl)benzyl]-4- aminopiperazine,3.5 parts of piperonal, 48 parts of 2- propanol, and 0.1 part of aceticacid is heated on a steam bath for 20 minutes. The mixture is allowed tocool and the crystals which form are separated and recrystallized from amixture of benzene and n-hexane to give l-[ -(Z- pyridyl)benzyl] 4(3,4-methylenedioxybenzalamino) piperazine rn'eltingatabout l4l-143 C.This compound has the following formula In the same way,l-'[u(3-pyridyl)benzyl]-4-aminopi- "perazineis reacted in the piperonalto give l-[a-(3-pyridyl] -4- 3 ,4-methylenedioxybenzalamino) piperazine.

CE CH Example 34 If an equivalent quantity of 4-nitrobenzaldehyde issubstituted for the Z-naphthaldehyde and the procedure of Example 15 isrepeated, the product is l-benzhydryl-4-(4- nitrobenzalamino)piperazinemelting at about 125-.

Example 35 1-benzhydryl-4-aminopiperazine is reacted with4-dimethylaminobenzaldehyde according to the procedure described inExample 25. The product obtained is l-benzhydryl-4-(4-dimethylaminobenzalamino piperazine melting'at about 179-181 C.

Example 36 An equivalent quantity of 4-acetamidobenzaldehyde issubstituted for the piperonal and the procedure of Example 25 isrepeated. The crude product is crystallized from benzene, washed with amixture of benzene and cyclohexane, and vacuum dried at C. This productis 1 (4 chlorobenZhydryl)-4-(4 acetamidobenzalamino)- piperazine and itmelts at about 188-1895 C.

Likewise, 4 propionamidobenzaldehyde reacts with 1-(4-chlorobenzhydryl)-4-aminopiperazine to give 1-(4- chlorobenzhydryl) 4(4 propionamidobenzalamino)- piperazine.

Example 37 The procedure of Example is repeated usingl-benzhydryl-4-arniuopiperazine and 4-cyanobenzaldehyde as thereactants. The crude product is recrystallized first from a mixture ofbenzene and n-heptane, twice from benzene, and then three times fromethyl acetate. The solid is finally dried at 100 C. under reducedpressure to give l-benzhydryl 4 (4-cyanobenzalamino)piperazine meltingat about 142-146 C. If 3-cyanobenzaldehyde is substituted for4-cyanobenzaldehyde in the above procedure, the product is1-benzhydryl-4-(3-cyanobenzalamino)piperazine.

Likewise, l-(4-chlorobenzhydryl)-4-aminopiperazine is reacted with4-cyanobenzaldehyde. The crude product is crystallized first from ethylacetate, then from a mixture of ethyl acetate and n-heptane, and finallyfrom absolute ethanol. The product is dried under vacuum at roomtemperature to give1-(4-chlorobenzhydryl)-4-(4-cyanobenzalamino)piperazine containing /3mole of ethanol of crystallization and melting at about 92-96 C. 1-(4-chlorobenzhydryl)-4-(3 cyanobenzalamino)piperazine is likewise obtainedfrom the reaction of 1-(4-chlorobenzhydryl)-4-aminopiperazine with3-cyanobenzaldehyde.

Example 38 The procedure of Example 27 is repeated but in this case4-cyan0benzaldehyde is reacted with 1-(2,2-dipheny1-ethyl)-4-aminopiperazine and with1-[2-(4-chlorophenyl)-2-phenylethy1]-4-aminopiperazine. The productsobtained are, respectively,1-(2,2-diphenylethyl)-4-(4-cyanobenzalamino)piperazine melting at about163-165 C. and 1-[2-(4-chlorophenyl)-2-phenylethyl] 4-(4-cyanobenza1-amino)piperazine melting at about 142-144 C.

Example 39 An equivalent quantity of terephthalaldehydic acid issubstituted for the Z-naphthaldehyde and the procedure of Example 15 isrepeated. The product is 1-benzhydryl-4-(4-carboxybenzalamino)piperazine melting at about 235- 236 C.

Example 40 An equivalent quantity of hydrocinnamaldehyde is substitutedfor the Z-naphthaldehyde and the procedure of Example 15 is repeated.The product is 1-benzhydryl- 4-hydrocinnamalaminopiperazine melting atabout 115- 117 C.

Example 41 An equivalent quantity of phenylacetone is substituted forthe piperonal and the procedure of Example is repeated. The productobtained is crystallized first from n-hexane and then from a mixture ofn-hexane and n-heptane to give1-(4-chlorobenzhydryl)-4-(1-methyl-2-phenylethylideneamino)piperazinemelting at about 144-147 C. This compound has the following formulaExample 42 1-benzhydryl-4-aminopiperazine is reated with cinnamaldehydeaccording to the procedure described in Example 9. The product obtainedis 1-benzhydryl-4-cinnarnalaminopiperazine melting at about 155-156 C.

Example 43 Reaction of 1-benzhydryl-4-aminopiperazine withdiphenylacetaldehyde according to the procedure described in Example 25gives l-benzhydryl-4-(2,2-diphenylethylidenearnino)piperazine melting atabout 118-119 C. after recrystallization from ethanol.

Example 44 1-(4-chlorobenzhydryl)-4-aminopiperazine is reacted withdiphenylacetaldehyde according to the procedure described in Example 15.To isolate and purify the product, the solvent is evaporated from thereaction mixture, the residue is dissolved in n-hexane, and the hexaneis evaporated to give a solid which is recrystallized from ethanol. Theproduct obtained in this way is 1-(4-chlorobenzhydryl) -4-(2,2-dipl1enylethyl ideneamino piperazine melting at about 138140.5 C.

Example 45 A mixture of 5 parts of 1 benzhydryl-4-aminopiperazine, 3.4parts of benzophenone, 265 parts of toluene, and 3 parts of4-toluenesulfonic acid is refluxed for 4 hours. The dark reactionmixture is washed with aqueous sodium hydroxide solution and then withwater and dried over anhydrous potassium carbonate. The residuecrystallizes partially on standing and is triturated with 2-propanol.The crude solid thus obtained is recrystallized from 2- propanol to give1-benzhydryl-4-(a-phenylbenzalamino) piperazine melting at about 143-145C.

Example 46 1-benzhydryl-4-(fluoren 9 ylideneamino)piperazine, melting atabout 184-187 C., is obtained from the reaction of 1benzhydryl-4aminopiperazine with fluorenone according to the proceduredescribed in Example 9. In this case, a drop of acetic acid is includedin the reaction mixture as catalyst.

Example 47 1-(4-chlorobenzhydryl)-4-aminopiperazine is reacted 'with9-anthaldel1yde using ethanol as the solvent and a drop of acetic acidas catalyst. The procedure is essen- :tially the same as that describedin Example 9. The crude product is recrystallized from ethyl acetate andthen dried at C. under reduced pressure to give 1-(4-chlorooenzhydryl)-4(9 anthrylmethyleneamino)piperazine melting at about -144 C.

Example 48 A mixture of 5 parts of 1-benzhydryl-4-aminopiperazine :andparts of acetone is heated on a steam bath until the excess acetone hasdistilled off. The residue crystallizes on standing and isrecrystallized from a minimum amount of acetone to give1-benzhydryI-4-isopropylideneaminopiperazine melting at about 113-114.5C. This compound has the following formula Example 491-benzhydryl-4-aminopiperazine is reacted with cyclohexanone accordingto the procedure described in Example 9. The product obtained is1-benzhyd1yl-4-cyclohexylideneaminopiperazine melting at about 119-121C.

Example 50 13 What is claimed is: 1. A compound of the formula phenylhalogen 3. 1-(4-chlorobenzhydryl) 4 benzalaminopiperazine. 4. A compoundof the formula (LLB.

wherein m is a whole number between 0 and 1 inclusive.

'8. 1 (4 ichlorobenzhydryl)-4-(3,4-methylenedioxybenzalamino)piperazine.

14 9. 1-[2-(4-chloropheny1) 2 phenylethyl] 4 (3,4-methylenedioxybenzalamino piperazzine.

10. A compound of the formula wherein m is a whole number between 0 and1 inclusive.

11. l-benzhydryl 4 (4 cyanobenzalamino) piperazine.

12. A compound of the formula wherein m is a whole number between 0 and1 inclusive.

13. 1-(4-ch1orobenzhydryl) 4 (4 cyanobenzalamino) piperazine.

References Cited in the file of this patent UNITED STATES PATENTS2,566,225 Mackay et al Aug. 28, 1951 2,663,706 Conroy Dec. 22, 19532,882,271 Janssen et al. Apr. 14, 1959 2,967,865 Rudner Jan. 10, 19613,035,976 Kimura May 22, 1962 3,054,791 Yale et al. Sept. 18, 19623,093,631 Grob et a1. June 11, 1963 3,098,066 Mull July 16, 19633,105,078 Ayer Sept. 24, 1963 FOREIGN PATENTS 715,236 Great BritainSept. 8, 1954 920,249 Germany Nov. 18, 1954 942,029 Germany Apr. 26,1956

1. A COMPOUND FO THE FORMULA
 2. A COMPOUND OF THE FORMULA